The long term objectives of this project are to characterize the equilibria and kinetics of the polymerization and gelation of sickle cell hemoglobin and, through understanding of this physical chemistry (which is responsible for pathogenesis), to develop a specific therapy for sickle cell disease. Specific aims concern kinetics, properties of the formed gel, and elucidation of relations between physical chemistry and clinical events. Kinetics will be examined principally by rheological methods, in some protocols in conjunction with optical methods, particularly light scattering. The course of increase of viscosity (and other properties) will be followed to ascertain the basic shape of the progress curve and in order to deduce mechanisms of gel assembly and values of the kinetic constants for the various reactions. Characterization will include ascertaining the distribution of hemoglobin S fiber lengths as the polymerization progresses. In addition, the effects of shearing on the kinetics will also be ascertained, as will the effects of solution conditions and various parameters which might have in vivo relevance. Since the gel is responsible for decreased red cell deformability and pathogenesis, its mechanical properties are important. Therefore, the solid-like, viscous and thixotropic properties of viscoplastic gels will be measured, as will equilibrium pressure-volume properties. Thermodynamic properties to be studied include phase relations in this two phase system, and the effects of various physiological moieties (2,3 diphosphoglycerate and protons) on gel properties. Studies will also be directed to the structure of hemoglobin S fibers and to liquid crystals, a basic element in the gel. These studies have many potential clinical relations. For example, shear occurs within red cells in the circulation, altering the vents of gelation markedly. Other factors, such as nuclei for gelation which are never melted upon oxygenation, may do the same. Thermodynamic properties such as the effects of 2,3 diphosphoglycerate and protons also may have significant clinical effects. In general, the kinetics of gelation are highly mutable with minor changes in conditions and the equilibria may be also somewhat mutable in cooperative fashion. If this lability is understood it may permit small physiological modifications which greatly ameliorate the course of sickle cell disease.